EP3192500B1 - Compositions for continuous administration of dopa decarboxylase inhibitors - Google Patents

Compositions for continuous administration of dopa decarboxylase inhibitors Download PDF

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EP3192500B1
EP3192500B1 EP17158360.2A EP17158360A EP3192500B1 EP 3192500 B1 EP3192500 B1 EP 3192500B1 EP 17158360 A EP17158360 A EP 17158360A EP 3192500 B1 EP3192500 B1 EP 3192500B1
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Prior art keywords
carbidopa
levodopa
arginine
administration
formulation
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EP3192500A1 (en
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Oron Yacoby-Zeevi
Mara Nemas
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Neuroderm Ltd
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Neuroderm Ltd
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Priority to PL17158360T priority Critical patent/PL3192500T3/pl
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
    • C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C243/18—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)

Definitions

  • the present invention relates to compounds and formulations useful in methods for treating diseases and disorders in which the dopamine level in the brain is reduced, e.g., Parkinson's disease.
  • the invention relates to a liquid composition comprising arginine and carbidopa.
  • Parkinson's disease is a degenerative condition characterized by reduced concentration of the neurotransmitter dopamine in the brain.
  • Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine) is an immediate metabolic precursor of dopamine that, unlike dopamine, is able to cross the blood-brain barrier, and is most commonly used for restoring the dopamine concentration in the brain. For the past 40 years, levodopa has remained the most effective therapy for the treatment of Parkinson's disease.
  • levodopa has a short half life in plasma that, even under best common current standard of care, results in pulsatile dopaminergic stimulation. Long-term therapy is therefore complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients.
  • a therapeutic strategy that could ultimately deliver levodopa/dopamine to the brain in a more continuous and physiologic manner would provide the benefits of standard levodopa with reduced motor complications and is much needed by patients suffering from Parkinson's disease and other neurological or movement disorders ( Olanow CW; Mov. Dis. 2008, 23(Suppl. 3):S613-S622 ).
  • levodopa The metabolic transformation of levodopa to dopamine is catalyzed by the aromatic L-amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain and brain capillaries. Due to the possibility of extracerebral metabolism of levodopa, it is necessary to administer large doses of levodopa leading to high extracerebral concentrations of dopamine that cause nausea in some patients.
  • levodopa is usually administered concurrently with oral administration of a dopa decarboxylase inhibitor, such as carbidopa or benserazide, which reduces by 60-80% the levodopa dose required for a clinical response, and thus prevents certain of its side effects by inhibiting the conversion of levodopa to dopamine outside the brain. Exactly how this dose reduction is accomplished is uncertain.
  • a dopa decarboxylase inhibitor such as carbidopa or benserazide
  • Various formulations comprising levodopa alone or together with inhibitors of enzymes associated with the metabolic degradation of levodopa are well known, for example, decarboxylase inhibitors such as carbidopa and benserazide, catechol-O-methyl transferase (COMT) inhibitors such as entacapone and tolcapone, and monoamone oxidase (MAO)-A or MAO-B inhibitors such as moclobemide, rasagiline or selegiline or safinamide.
  • decarboxylase inhibitors such as carbidopa and benserazide
  • catechol-O-methyl transferase (COMT) inhibitors such as entacapone and tolcapone
  • MAO monoamone oxidase
  • MAO-A or MAO-B inhibitors such as moclobemide, rasagiline or selegiline or safinamide.
  • WO 2006/006929 relates to an infusion or injection solution of levodopa containing at least 10 mg/mL of levodopa, or at least 5 mg/mL of levodopa together with at least 0.5 mg/mL of at least one inhibitor of a levodopa-metabolizing enzyme.
  • the solution further contains a buffer, a physiologically acceptable sugar, such as glucose, a physiologically acceptable acid, such as hydrochloric acid, and optionally a stabilizer, and has a pH of lower than or equal to 6.
  • US 2005/070608 relates also to a liquid solution of 2.5-6% Carbidopa with pH as low as possible.
  • paragraph [130] "The results indicate that lowering the pH of the formulation increases stability of carbidopa".
  • available oral drugs include SINEMET® and SINEMET®CR sustained-release tablets that include carbidopa or levodopa; STALEVO® tablets containing carbidopa, entacapone and levodopa; and MADOPAR® tablets containing levodopa and benserazide.
  • Carbidopa [(-)-L-a-hydrazino-a-methyl-p-(3,4-dihydroxybenzene) propanoic acid monohydrate], a white, crystalline compound, only slightly soluble in water, is a dopa decarboxylase inhibitor commonly administered with levodopa. Only 40-70% of an oral dose of carbidopa is absorbed in man, monkey and dog. Although carbidopa has been orally administered with levodopa for over 30 years, no stable liquid formulation having e.g., an effective concentration in a volume suitable for use for subcutaneous or transdermal delivery has ever been achieved. There is an urgent, long standing need for such carbidopa formulations that can be administered more easily to patients, especially as compared to current invasive modes such as duodenal administration.
  • an arginine salt of carbidopa can form a stable, liquid formulation, suitable for e.g., continuous subcutaneous, transdermal, intradermal, intravenous and/or intraduodenal administration, at a physiologically acceptable pH.
  • Such disclosed compositions are capable of substantially continuously administering carbidopa to a patient.
  • substantially continuously administering a dopa decarboxylase inhibitor such as carbidopa may stimulate L-dopa substantially continuously and thus e.g., extend the effectiveness of a levodopa oral dosing regimen and/or reduce the daily dosage of levodopa, while effectively treating a movement and/or neurological disorder such as Parkinson's disease.
  • the present disclosure relates, in one aspect, to an arginine salt of an active agent selected from carbidopa and levodopa that are suitable for e.g., continuous subcutaneous, transdermal, intradermal, intravenous, oral, or intraduodenal administration.
  • liquid e.g., liquid at room temperature
  • gel formulations or compositions that include an arginine salt of carbidopa, e.g., include carbidopa and arginine
  • Such contemplated liquid compositions may include in one embodiment at least 1%, at least 4% by weight carbidopa, (e.g.
  • contemplated herein is a liquid or gel composition that includes a molar ratio of about 1.0:0.5 to about 1: to about 2.5, e.g., 1: 1.0-1.2 molar ratio of carbidopa:basic amino acid, e.g. carbidopa:arginine.
  • a liquid composition that includes carbidopa and arginine, as contemplated herein, has a physiologically acceptable pH, e.g. a pH of about 6.5 to 9.5, e.g., about 7 to about 9, or about 8 to about 9, at 25 °C.
  • contemplated herein is a pharmaceutically acceptable liquid or gel composition that includes a molar ratio of about 1.0:0.5 to about 1:2, e.g., about 1:1.8 molar ratio of levodopa:arginine.
  • a liquid composition that may include at least about 4% by weight, or at least 5%, at least about 6% (e.g. about 3% to about 7%) or more by weight levodopa.
  • a liquid composition having levodopa and a basic amino acid, as contemplated herein, may have a pH of about 8 to 10, e.g., about 8.5 to about 9.5, at 25°C.
  • Exemplary liquid compositions contemplated herein may be liquid solutions, e.g. may be a substantially homogenous mixture that includes carbidopa and arginine, and may include water, or alternatively may be substantially non-aqueous.
  • contemplated compositions may also include one or more pharmaceutically acceptable excipients such as N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, antioxidants, or combinations thereof.
  • NMP N-methylpyrrolidone
  • PVP polyvinylpyrrolidone
  • propylene glycol antioxidants, or combinations thereof.
  • the pharmaceutically acceptable liquid composition of the invention may comprise additional active agents such as entacapone or tolcapone.
  • kits comprising: a) a first composition suitable for continuous administration comprising the liquid or gel formulation of the invention comprising an arginine salt of carbidopa; b) a second composition suitable for oral administration comprising levodopa or a pharmaceutically acceptable salt or ester thereof; and c) optionally instructions administration of the first formulation in conjunction with the second formulation.
  • the first composition in the kit for continuous administration of the arginine salt of carbidopa may be formulated for transdermal, intradermal, subcutaneous, intravenous, or intraduodenal administration such as by using an infusion pump.
  • the second composition in the kit i.e., the levodopa composition may comprise levodopa, a pharmaceutically acceptable salt of levodopa., preferably an arginine salt thereof as disclosed herein, or may be a composition that includes levodopa and further comprises one or more decarboxylase inhibitors such as carbidopa and/or benserazide, or one or more catechol-O-methyl transferase (COMT) inhibitors such as entacapone and/or tolcapone, or one or more MAO-A or MOA-B inhibitors such as selegiline and/or rasagiline, or combination thereof.
  • levodopa composition may comprise levodopa, a pharmaceutically acceptable salt of levodopa., preferably an arginine salt thereof as disclosed herein, or may be a composition that includes levodopa and further comprises one or more decarboxylase inhibitors such as carbidopa and/or be
  • a decarboxylase inhibitor a salt thereof, e.g., an arginine salt of carbidopa, or an ester thereof for use in a method for treatment of a disease or disorder characterized by reduced levels of dopamine in a patient's brain (e.g.
  • Parkinson's disease comprising substantially continuously administering to a patient in need thereof a therapeutically effective amount of the decarboxylase inhibitor, a salt thereof, e.g., an arginine salt of carbidopa, or an ester thereof, and administering a therapeutically effective amount of levodopa or pharmaceutically acceptable salt thereof (e.g., arginine levodopa), or composition comprising levodopa (for example, administering a composition e.g.
  • levodopa as its sole active agent, or a composition that includes levodopa and one or more other active agents such as carbidopa, benserazide, entacapone, tolcapone, selegiline and/or rasagiline.
  • a carbidopa basic amino acid salt e.g., carbidopa arginine
  • composition comprising carbidopa and arginine may be administered substantially continuously and/or the composition comprising levodopa may be administered at discrete intervals (for example by oral administration one, two, three or more times a day), during the substantially continuous administration of composition comprising a carbidopa arginine salt.
  • Also provided according to the present disclosure is a method of substantially continuously inhibiting decarboxylase activity and/or a method of increasing the half-life of levodopa in a patient receiving levodopa, comprising administering (e.g. substantially continuously) to the patient a liquid or gel composition comprising a carbidopa salt such as carbidopa arginine.
  • the disclosed methods may result in a half-life of levodopa in the plasma of a patient that is at least 1.5, or at least two times, longer after continuous administration of carbidopa as compared to the half life of levodopa in a patient's serum after administering levodopa with discrete, oral administration of carbidopa.
  • a liquid composition having a physiologically acceptable pH that includes an arginine salt of carbidopa (e.g., arginine and carbidopa) that is stable at room temperature, which can facilitate continuous delivery of an effective amount carbidopa to a patient in a minimally invasive fashion (e.g. a disclosed liquid formulation comprises a significantly high concentration of carbidopa so that administration of large amounts of liquid are not required)
  • Such formulations may facilitate continuous decarboxylase inhibition which prolongs the half life of levodopa.
  • results from in vivo studies, as described below, in which L-dopa was administered continuously in parallel with oral administration of carbidopa every 6-8 hours demonstrate a pulsatile pattern of L-dopa plasma levels that coincide with carbidopa oral dosing regimen, but concomitant and/or frequently repeated, e.g., simultaneous dosing of dopa decarboxylase inhibitor (e.g. of carbidopa or a salt thereof, or benserazide) with or without COMT inhibitors with discrete or continuous administration of levodopa is more effective in the treatment of e.g., Parkinson's disease.
  • dopa decarboxylase inhibitor e.g. of carbidopa or a salt thereof, or benserazide
  • the pharmacokinetic profile of, for example, carbidopa supports such new therapies that include substantially continuous administration of dopa decarboxylase inhibitors (e.g. benserazide or carbidopa or a salt thereof) with or without COMT inhibitors together with administration (continuous or at discrete intervals) of e.g. levodopa or a salt thereof.
  • dopa decarboxylase inhibitors e.g. benserazide or carbidopa or a salt thereof
  • COMT inhibitors continuous or at discrete intervals
  • formulations of carbidopa that unexpectedly allow for stable dissolution of higher concentrations (e.g., greater than 1% by weight) of carbidopa and/or levodopa at e.g. physiologically acceptable pH, for e.g., substantially continuous subcutaneous or transdermal administration.
  • Such formulations may also be suitable for intravenous, intradermal, oral or intraduodenal administration.
  • formulations and methods capable of obtaining substantially constant inhibition of dopa decarboxylase activity upon administration, thereby increasing the half life of administered levodopa and substantially reducing the pulsatility of levodopa plasma levels to avoid low trough levels of plasma levodopa.
  • a treatment strategy of continuous carbidopa administration in accordance with the present invention may simulate L-dopa substantially continuously.
  • therapies and/or methods of the present invention may extend a levodopa oral dosing regimen to about 2 to about 3 times/day, and/or reduce daily dose of levodopa, and/or reduce or even eliminate the risk of motor complications associated with standard oral levodopa formulations in Parkinson's patients.
  • a pharmaceutically acceptable formulation that includes a carbidopa arginine salt that allows for substantially continuous administration of carbidopa.
  • a carbidopa free base is practically insoluble in alcohol, chloroform or ether and only slightly soluble in water
  • a stable liquid formulation that includes carbidopa and may be suitable for substantially continuous administration to a patient.
  • such formulations may have a physiologically acceptable pH.
  • the present disclosure relates to a carbidopa arginine salt.
  • a liquid formulation comprising a carbidopa salt of the invention.
  • a disclosed carbidopa arginine salt may be dissolved in an aqueous solution, e.g., having a pH of about 6 to 9.5, preferably from about 7 to about 9, more preferably from about 8 to 9 at 25°C or at 30°C.
  • carbidopa (free base) and arginine are dissolved together in a liquid (e.g. an aqueous liquid) to form a disclosed liquid formulation.
  • Disclosed liquid formulations may include about 1.0% by weight or more carbidopa or carbidopa arginine salt, for example, may include about 0.5% to about 6% by weight carbidopa.
  • a liquid formulation may include carbidopa and arginine in molar ratio of about 1: 0.5 to about 1:2.5, or about 1:1 to about a 1:1.2, e.g., about 1:1 or 1:1.1.
  • Disclosed liquid formulations may be stable for 24 hours, for 48 hours, for 7 days, or more at 25°C.
  • an exemplary liquid formulation may include a 1:1.1 molar ratio of carbidopa:arginine, with about 2% to about 6% by weight carbidopa.
  • Such a carbidopa:arginine liquid formulation may be more stable at 7 days as compared to a liquid composition that includes a lysine or histidine salt of carbidopa.
  • disclosed liquid formulations or compositions are liquid solutions, i.e. are substantially homogenous liquid mixtures. Such liquid mixtures may comprise water and/or other excipients. In another embodiment, disclosed liquid compositions may be substantially non-aqueous.
  • a stable liquid solution can be unexpectedly formed from carbidopa and arginine.
  • a solution is stable at room temperature, e.g., is a substantially clear solution, even at high carbidopa concentrations of 2, 3, 4, 6 weight percent carbidopa.
  • Such solutions e.g. up to about 6 weight percent carbidopa, are stable (e.g., no precipitation) at least for 48 hours.
  • such disclosed solutions even at high concentrations of carbidopa, have a physiologically acceptable pH, such solutions can be adjusted to an appropriate pH, but still have a significant amount of carbidopa in a smaller volume so that it facilitates patient administration, without e.g. administering large volumes of solution.
  • solutions having carbidopa and arginine are unexpectedly more stable even as compared to solutions of carbidopa with other basic amino acids such as histidine or lysine, as shown below in e.g. Example 6.
  • Contemplated liquid formulations may, in some embodiments, further comprise levodopa or levodopa and arginine, and/or optionally a catechol-O-methyl transferase (COMT) inhibitor, such as entacapone or tolcapone; and/or a monoamine oxidase (MAO)-A or MAO-B inhibitor, such as moclobemide, rasagiline, selegiline or safinamide.
  • a catechol-O-methyl transferase (COMT) inhibitor such as entacapone or tolcapone
  • MAO monoamine oxidase
  • MAO-A or MAO-B inhibitor such as moclobemide, rasagiline, selegiline or safinamide.
  • a liquid formulation comprising an arginine salt of levodopa, or a liquid formulation comprising arginine and levodopa.
  • a liquid formulation that includes levodopa and arginine in a molar ratio of about 1:1.5 to about 1:2.5, or about 1: 1.8 to about 1.20.
  • levodopa and arginine formulations or solutions may have a pH of about 8 to about 10, for example, about 8.5 to about 9.5.
  • a disclosed formulation having levodopa and arginine may include about 2%, 3%, 4%, 5%, 6% or more by weight levodopa, e.g., may include about 4% or more by weight levodopa.
  • a disclosed liquid formulation will be stable for a period of 1 day, 2 days, 3 days, 1 week, or 1 month or more at room temperature.
  • a disclosed liquid formulation further comprise a pharmaceutically acceptable excipient such as e.g., N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propyleneglycol, or a combination of one or more thereof, and may further comprise one or more antioxidants such as, but not limited to, N-acetyl cysteine, sodium bisulfite, gluthatione, and ascorbic acid.
  • NMP N-methylpyrrolidone
  • PVP polyvinylpyrrolidone
  • propyleneglycol propyleneglycol
  • antioxidants such as, but not limited to, N-acetyl cysteine, sodium bisulfite, gluthatione, and ascorbic acid.
  • the present invention provides a stable liquid formulation that comprises about 0.5 to about 6% carbidopa, about 0.25 to about 20% arginine, about 0 to about 30% NMP, about 0 to about 5% PVP, and/or about 0 to about 5% of one or more water soluble antioxidants, by weight.
  • the disclosure further provides a stable lyophilized powder comprising a carbidopa arginine salt.
  • a stable lyophilized powder may comprise about 20-99% of the carbidopa salt, about 0-60% NMP, about 0-15% PVP, and about 0-5% of one or more water soluble antioxidants.
  • the lyophilized powder can be reconstituted into a liquid formulation by addition of water alone or water with NMP, and may include or not include antioxidants.
  • Liquid formulations of the present disclosure may be designed for continuous administration of a carbidopa or levodopa salt to a patient in need thereof.
  • a patient may be substantially continuously administered (e.g. subcutaneously, transdermally, intraduodenally, intradermally, or intravenously) a formulation that includes the disclosed carbidopa arginine salt, while levodopa, a levodopa salt, or a composition comprising levodopa is orally administered at discrete intervals, e.g., 2, 3, 4, or 5 times a day.
  • a composition comprising levodopa contemplates formulations that comprise levodopa, optionally together with one or more decarboxylase inhibitors, one or more catechol-O-methyl transferase (COMT) inhibitors, and/or one or more MAO-A or MAO-B inhibitors.
  • a composition comprising levodopa may include a dosage formulation that comprises levodopa (or a salt thereof) and optionally one or more other drugs, where the dosage formulation may be an immediate release, controlled release, dual release or multiple release formulation suitable for oral administration.
  • decarboxylase inhibitor refers to a dopa decarboxylase (DDC) inhibitor, e.g., a drug that inhibits the peripheral metabolism of levodopa to dopamine by aromatic L-amino acid decarboxylase such as carbidopa and benserazide.
  • DDC dopa decarboxylase
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • physiologically acceptable pH is understood to mean a pH of e.g., a composition that facilitates administration of the composition to a patient without significant adverse effects, e.g. a pH of about 4 to about 9.
  • compositions comprising levodopa contemplated herein may also include a decarboxylase inhibitor (carbidopa or benserazide) and entacapone, e.g. "triple therapy”.
  • a decarboxylase inhibitor carbidopa or benserazide
  • entacapone e.g. "triple therapy”.
  • MAO-A or MAO-B inhibitors refer to inhibitors that prevent the breakdown of dopamine by monoamine oxidases A or B, e.g., moclobemide, rasagiline, selegiline or safinamide, more preferably, rasagiline.
  • kits comprising: a) a first formulation comprising a carbidopa arginine salt and/or carbidopa and arginine, wherein said first formulation is suitable for continuous administration; b) a second formulation comprising levodopa or an arginine salt of levodopa, wherein said second formulation is suitable for oral administration; and c) instructions for administration of formulation a) in conjunction with formulation b).
  • the formulation a) comprising the carbidopa salt may be suitable for continuous administration by any suitable route such as transdermally, intravenously, subcutaneously, intradermally, intramuscularly or intraduodenally.
  • the first formulation of the disclosed kit comprising the carbidopa salt may be liquid or a lyophilized powder that can be reconstituted into a liquid formulation, or, for example, may form part of a transdermal patch, and may be designed for continuous administration by any suitable route such as, but not limited to, transdermally, intravenously, subcutaneously, intradermally, intramuscularly or intraduodenally.
  • the first formulation comprises the disclosed carbidopa arginine salt and is suitable for administration subcutaneously.
  • the second formulation of the disclosed kit may include the levodopa, a levodopa ester, a levodopa salt, or a composition comprising levodopa, and may be presented as any suitable oral dosage such as, but not limited to, pills, tablets, dispersible tablets, capsules, liquid, and the like.
  • the second formulation may be in the form of an immediate release, controlled release or dual release oral formulation that comprises both levodopa and benserazide, or both levodopa and carbidopa.
  • Such oral formulation in the form of pills, tablets, or the like may comprise a ratio of carbidopa or benserazide to levodopa of about 1:10 to 1:4, preferably from about 1:4 to 1:1.
  • Other disclosed second formulations include formulations, e.g., tablets that include levodopa, carbidopa, and entacapone, or e.g. a tablet that includes levodopa arginine salt and/or carbidopa arginine salt.
  • the kit comprises a first liquid formulation comprising carbidopa and arginine suitable for, but not limited to, transdermal, intravenous, subcutaneous, intradermal, intramuscular, intraduodenal continuous administration, and a second formulation in the form of an immediate release, controlled release or dual release oral formulation comprising levodopa and carbidopa.
  • the oral formulation in the form of pills, tablets, or the like may comprise a ratio of carbidopa to levodopa from about 1:10 to about 1:4, preferably from about 1:4 to about 1:1.
  • the present disclosure relates to a formulation comprising a carbidopa ester such as, but not limited to, the ethyl, propyl, isopropyl or hexyl ester of carbidopa, and salts thereof.
  • a carbidopa ester such as, but not limited to, the ethyl, propyl, isopropyl or hexyl ester of carbidopa, and salts thereof.
  • levodopa esters contemplated herein include the alkyl esters, e.g., the methyl, ethyl, propyl, or isopropyl ester, or the benzyl ester.
  • compositions of the present disclosure are useful for treatment of a disease or disorder characterized by reduced and/or fluctuating levels of dopamine in a patient's brain when co-administered substantially continuously to a patient in need together with a therapeutically effective amount of levodopa or salt thereof or a composition comprising levodopa.
  • a therapeutically effective amount of levodopa or salt thereof or a composition comprising levodopa As shown in the Examples, separate continuous administration of carbidopa, together with administration of levodopa, even with discrete (e.g. oral) administration of levodopa, to a patient results in significantly higher levels of levodopa in the plasma of a patient upon administration as compared to a current standard of discrete carbidopa and levodopa simultaneous dosing.
  • disclosed methods may result in a half-life of levodopa in the plasma of a patient that is at least 1.5, or at least two times, longer after continuous administration of carbidopa as compared to the half life of levodopa in a patient's serum after administering levodopa without continuous administration of carbidopa (e.g., with discrete, oral administration).
  • Contemplated therapies are intended to embrace administration of multiple therapeutic agents in a manner wherein a dopa decarboxylase inhibitor is administered substantially continuously while levodopa is administered at discrete intervals, as well as administration of contemplated therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Administration can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, intradermal routes, subcutaneously, transdermally, and direct absorption through mucous membrane tissues.
  • levodopa can be administered by the same route or by different routes as compared to administration of e.g. a contemplated carbidopa formulation.
  • carbidopa may be administered subcutaneously, e.g., substantially continuously, while levodopa may be administered orally, e.g. at discrete intervals.
  • a disclosed liquid carbidopa composition e.g. having carbidopa and arginine
  • an oral composition that includes levodopa and may also include one or more other active agents such as a dopa decarboxylase inhibitor
  • both levodopa and carbidopa may be administered subcutaneously or transdermally.
  • the disease or disorder characterized by reduced levels of dopamine in the brain contemplated herein are neurological or movement disorders including restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication.
  • the disease to be treated is Parkinson's disease.
  • the contemplated decarboxylase inhibitor is the arginine salt of carbidopa.
  • a disclosed carbidopa/arginine formulation may be administered substantially continuously using e.g. a liquid formulation, for example, via a pump for subcutaneous infusion (insulin pump) at an average rate of about 10-250 ⁇ 1/hour, preferably about 15-85 ⁇ 1/hour, in conjunction with oral administration of levodopa, an arginine salt of levodopa, or composition comprising levodopa.
  • a pharmaceutically effective amount of a composition comprising carbidopa and arginine can be administered substantially continuously to a patient for treating a neurological or movement disorder e.g., Parkinson's disease, while the second composition of the kit comprising levodopa or a salt thereof, e.g., the levodopa arginine salt, is administered non-continuously to the patient.
  • a neurological or movement disorder e.g., Parkinson's disease
  • the second composition of the kit comprising levodopa or a salt thereof, e.g., the levodopa arginine salt is administered non-continuously to the patient.
  • the composition comprising a carbidopa and arginine may be liquid at room temperature.
  • the composition may be administered substantially continuously over 12 hours, 1 day, 1 week, or more.
  • the composition comprising levodopa additionally disclosed herein may form all or part of an immediate release, controlled release, or dual release oral formulation comprising levodopa and optionally benserazide or carbidopa, and may be administered 1, 2, 3, or 4 or more times a day, for example, by oral administration (e.g. by tablet).
  • a levodopa salt for use in a method for treatment of a disease or disorder characterized by reduced levels of dopamine in a patient's brain, (e.g., Parkinson's disease) comprising co-administering substantially continuously to a patient in need a therapeutically effective amount of the disclosed levodopa salt.
  • a disease or disorder characterized by reduced levels of dopamine in a patient's brain e.g., Parkinson's disease
  • Carbidopa (CD)-Arginine salt was prepared as follows: Carbidopa [Teva Pharmaceuticals Ltd., Israel] was weighed in a suitable container with L-arginine [Merck] (at molar ratio of 1:1) and a 0.2% sodium bisulfite [Sigma] solution in water was added to obtain a final concentration of 4.0% carbidopa. The mixture was heated to 65 ⁇ 10°C with constant stirring. When the solids were completely dissolved, solution was filtered using 0.45 ⁇ M nylon membrane. The filtered solution was immediately frozen in dry ice and subsequently subjected to lyophilyzation. Off-white crystals were obtained and subsequently subjected to MS analysis.
  • a 6% Carbidopa solution/formulation was prepared as follows: Carbidopa [Teva Pharmaceuticals Ltd, Israel] and L-arginine [Merck] (molar ratio 1:1.1) were weighed in a suitable container and water was then added to obtain 84% of the total projected batch weight. N-methyl 2-pyrrolidone [Pharmasolve, ISP] was added to obtain the final concentration of 5% (w/w) sodium bisulfite [Sigma] solution was prepared and added to obtain a final concentration of 0.1% (v/w). The mixture was heated to 65 ⁇ 10°C with constant stirring. When the solids were completely dissolved heating was stopped and the preparation was allowed to cool down to room temperature. Solution was filtered using a sterile 0.22 ⁇ M PVDF membrane.
  • Carbidopa formulation was prepared as follows: Carbidopa [Teva] and L-arginine [Merck] (molar ratio 1:1) were weighed in a suitable container and propylene glycol [Merck] was added to obtain 75% of the total projected batch weight. Sodium bisulfite [Sigma] solution was prepared and added to obtain a final concentration of 0.05%. The mixture was heated to 65 ⁇ 10°C with constant stirring. When the solids were completely dissolved, heating was stopped and the preparation was allowed to cool down to room temperature. PEG-400 [Merck], 10% of the total projected batch weight, was added. The pH was adjusted to 7.5 with 85% lactic acid [Fluka].
  • Table 1 indicates the solubility and stability of carbidopa in these aqueous solutions with basic amino acids (arginine, lysine or histidine) as determined visually (Table 1A) or by UV HPLC (Table 1B).
  • arginine a stable solution of 6% carbidopa was prepared, whereas a solution with only less than 4% could be formulated with lysine (Table 1A).
  • Levodopa (LD)-arginine salt was prepared as follows: Levodopa [Teva] was weighed in a suitable container with L-arginine [Merck] (at molar ratio of 1:1.8) and a 0.2% sodium bislfite [Sigma] solution in water was added to obtain a final concentration of 4.4% L-Dopa. The mixture was heated to 65 ⁇ 10°C with constant stirring. When the solids were completely dissolved, solution was filtered using 0.45 ⁇ M nylon membrane. The filtered solution was immediately frozen in dry ice and subsequently subjected to lyophilization. The filtered solution was immediately frozen in dry ice and subsequently subjected to lyophilyzation. Off-white crystals were obtained and subsequently subjected to MS analysis.
  • a 10 % carbidopa (Reference Example) and 4/6% carbidopa/entacapone solutions/ formulations were prepared as follows: Carbidopa [Assia Ltd.] was weighed in a suitable container and water was then added to obtain 73% of the total projected batch weight. Mixture was stirred at room temperature for 20 minutes. L-Arginine [Sigma] was added to the mixture to obtain a molar ratio 1:1 with Carbidopa. The mixture was heated to 65 ⁇ 10°C with constant stirring. When the solids were completely dissolved, N-methyl 2-pyrrolidone [Pharmasolve, ISP] was added to obtain the final concentration of 10% (w/w).
  • Entacapone [extracted from Comtan®, Novartis] was added to the 4% carbidopa solution to obtain a final concentration of 6% (w/v). Both formulations (10% CD and 4/6% CD/E) were continuously administered sc to pigs for a period of 21h to evaluate potential local reactions. Macroscopic and microscopic evaluations indicated that 21h continuous subcutaneous administration of these carbidopa solutions/formulations was safe. (Table 2).
  • Table 2 indicates the results of a histological evaluation of skin biopsies obtained from female Landrace ⁇ large white swine following continuous subcutaneous administration of 10% CD (carbidopa) or 4/6% CD/entacapone for a period of 21h, at a rate of 25 or 82 ⁇ l/h.
  • Pigs weighing 30-35 kg were administered orally with either Stalevo ® (Novartis, 100/25/200 mg, LD/CD/E), Dopicar® [Teva] + Lodosyn® (Merck & Co) (125/25 mg, LD/CD) or Sinemet CR® (MSD,100/25 mg, LD/CD) thrice or twice daily (q8 or 12h, respectively) with or without carbidopa (60 mg/pig/d) for a total period of 68h. Blood samples were collected at pre-determined time points and plasma levels of L-dopa and carbidopa were analyzed by LC-MS.
  • results showed that the co-administration of continuous subcutaneous carbidopa with any oral LD preparation significantly increases (more than ⁇ 2) the half live (t1 ⁇ 2) and AUC of levodopa.
  • increased carbidopa oral dose or frequency did not considerably improve the PK profile of levodopa, as shown in Table 3.
  • constant, steady-state, levels of CD was maintained at 164 ⁇ 34 ng/ml during the 68 hours of continuous SC administration of carbidopa (60 mg/pig/day). This was in opposition to the fluctuating pattern and very low trough levels of CD obtained after administration of standard treatment ( Figs. 3A-3C ). No signs of treatment related local or systemic toxicity were observed throughout the entire 68h study period.
  • the purpose was to determine the effect of continuous subcutaneous administration of carbidopa (15 mg/kg/d) on the levels of levodopa and dopamine in the brain following oral administration of levodopa/carbidopa (32/8 mg/kg TID) in mice.
  • mice were implanted subcutaneously with Alzet pumps containing Saline (Negative Control), Vehicle or Carbidopa solution.
  • a day following implantation LD/CD was administered orally q8h.
  • the level of levodopa and dopamine in the brain was determined following the 4 th oral dose of LD/CD.
  • the results showed dopamine levels seven hours post-administration of oral LD to be significantly higher in the brains of mice continuously administered SC with carbidopa ( Fig. 4A ), concurrently with higher levels of plasma LD ( Fig. 4B ).
  • Pigs weighing 30-35 kg were administered orally with Sinemet® (Merck & Co., 100/25 mg, LD/CD,), thrice daily (q8h), or Dopicar® (Teva) + Lodosyn® (Merck & Co., (125/25 mg LD/CD), twice daily (q12h), with continuous subcutaneous vehicle, 2% or 4% carbidopa (0, 40 or 80 mg/pig/d, respectively) for a total period of 24h. Blood samples were collected at pre-determined time points and plasma levels of L-dopa and carbidopa were analyzed by LC-MS. Skin biopsies were collected from the infusion sites immediately, 1 and 2 weeks post-administration and local tolerance was evaluated by histological analysis of H&E stained slides. No histological treatment-related abnormalities were observed at the sites of infusion.
  • the purpose was to determine the plasma levels of L-dopa, following co-administration of oral L-dopa/Carbidopa with continuous subcutaneous administration of another DDC inhibitor, benserazide. Plasma levels of L-dopa were measured by HPLC-ECD.
  • Example 14 (Reference Example) - The Transdermal Delivery of Carbidopa Propyl Ester (CDPE) Through Full Thickness Pig Skin Ex-Vivo using the Franz Cell Delivery System.
  • CDPE Carbidopa Propyl Ester
  • the purpose was to determine the transdermal delivery of carbidopa propyl ester through a full thickness porcine skin, ex vivo using the Franz cell delivery system.
  • Gel formulations containing CDPE were prepared. Samples were collected from the receiver cell at time 0, 16, 19 and 22 hours after formulation application on to the skin. The amount of CD compounds in the receiver cell fluid was determined by a spectrophotometer at 280 nM. The results shown in Fig. 9 demonstrate that CDPE penetrates the skin in an enhancer-dose dependent manner.
  • LD and CD administered orally as arginine salts, either enteric-coated or not.
  • Pigs were orally administered with 255/45 mg LD-arginine salt (LDs)/CD-arginine salt (CDs) to 30-35kg pigs in gelatin coated or non-coated capsules (corresponding to 100/25 LD/CD).
  • Plasma levels of LD and CD were measured by HPLC-ECD.
  • Figs. 10A-10B showed that LDs and CDs were absorbed more rapidly and efficiently as compared to LD/CD (Sinemet®), and that oral administration of enteric coated LDs/CDs extended the PK of plasma LD (10A) and CD (10B).
  • CDEs carbidopa esters
  • DDC enzymes were obtained from porcine liver homogenate and their activity was measured by comparing LD concentrations with and without carbidopa propyl ester (CDPE). Liver homogenate preparation was based on the method described by Umezawa et al; (J. Antib. 1975, 28(12):947-52 ).
  • Figs. 11 and 12A-12B demonstrate that CDPE inhibits the decarboxylation of L-dopa to dopamine, in a similar manner to carbidopa and benserazide.

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